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PubMed1993

Effects of AMP and fructose 2,6-bisphosphate on fluxes between glucose 6-phosphate and triose-phosphate in renal cortical extracts.

Gluconeogenic flux exceeds glycolytic flux at the hexose-phosphate steps when measured in extracts of kidney cortex from well-fed rats. Addition of AMP and/or fructose 2,6-bisphosphate to the assay medium partially eradicates the difference. Using principles developed by Kacser, H., and Burns, J. A. ((1973) in Rate Control of Biological Processes (Davies, D. D., ed) pp. 65-104, Cambridge University Press, London) and Heinrich R., and Rapoport T. A. ((1974) Eur. J. Biochem. 42, 97-105), flux control coefficients of enzymes participating in the pathway segments from glucose 6-phosphate to triose-phosphates and from glycerol 3-phosphate to glucose 6-phosphate were determined by additions of the respective enzyme to the system. Results show that the flux control coefficients are highly modulated by the presence of allosteric effectors, as might be expected according to the regulatory properties of phosphofructokinase and fructose-1,6-bisphosphatase purified from this origin. Measured reductions of fructose 2,6-bisphosphate and AMP levels during acidosis, starvation, or after phenylephrine treatment suggest that these changes contribute to enhanced gluconeogenesis under these conditions.

Adenosine Monophosphate↗
PubMed1993

Cold-sensitive cytosolic 3,5,3'-triiodo-L-thyronine-binding protein and pyruvate kinase from human erythrocytes share similar regulatory properties of hormone binding by glycolytic intermediates.

Similar cold-sensitive properties, values of dissociation constants (Kd = 1 x 10(-10) M), and regulatory effectors were found for the cold-sensitive cytosolic 3,5,3'-triiodo-L-thyronine (L-T3)-binding protein (CTBP) and pyruvate kinase from human erythrocyte. Various metabolites of the blood cell were assayed for their effects on CTBP activity after heat and cold preincubation treatments. Among these compounds, five- and six-carbon phosphorylated sugars were effective in protecting the CTBP activity against cold inactivation, whereas only ATP and dATP blocked activation by heat treatments. The effects of fructose 1,6-bisphosphate, fructose 2,6-bisphosphate, and ATP were obtained at physiological concentrations. Three-carbon phosphorylated intermediates of glycolysis, ADP, AMP, cAMP, and GTP had no effect on cold and heat treatments. The monomer-tetramer interconversion of the enzyme was also regulated by fructose 1,6-bisphosphate and ATP. The association is under the control of fructose 1,6-bisphosphate, whereas the dissociation is under ATP control. This regulation may have physiological relevance since the hormone binds to the tetrameric form of the enzyme at a site other than the active site.

Adenosine Triphosphate↗
PubMed1993

Isozyme-specific modules on human aldolase A molecule. Isozyme group-specific sequences 1 and 4 are required for showing characteristics as aldolase A.

Vertebrate aldolase molecules bear at least four stretches of isozyme group-specific sequences (referred to as IGS). The IGSs of the type A isozyme are known to endow the aldolase molecules with some characteristics typical of A. In order to locate the type A regions, 4 chimeric enzymes were constructed between human aldolases A and B and 5 mutant enzymes with single or double mutations in the IGS-1 region. Among engineered proteins, the chimeric enzymes bearing the type A IGS-1 to -4 (BABA34-108:306-363) and the IGS-1 and -4 (BABA34-55:306-363) exhibited similarities to isozyme A in many respects. On the other hand, neither chimeric enzyme bearing the type A IGS-1 to -3 (BAB34-108) nor that bearing the IGS-1 alone (BAB34-55) exhibited properties as isozyme A. Four mutant aldolases A (carrying single mutation in the IGS-1 region) maintained the original activity as A. Similarly, the BA306 chimera with the type B-->A substitution at positions 41 and 45 (BA306 N41K:R45S) failed to exhibit the A-like properties although the activities toward Fru-1,6-P2 and Fru-1-P significantly increased. Conclusively, the type A IGS-1, together with the IGS-4, act as indispensable modules in determining the characteristic properties of human aldolase A.

Amino Acid Sequence↗
PubMed1993

Role of fructose 2,6-bisphosphate in the control of glycolysis. Stimulation of glycogen synthesis by lactate in the isolated working rat heart.

Fructose 2,6-bisphosphate (Fru-2,6-P2) is the most potent stimulator of 6-phosphofructo-1-kinase (PFK-1), a key enzyme of glycolysis. We studied whether this regulator is involved in the changes of glycolysis that can be induced experimentally in the isolated working rat heart. The glycolytic flux was assessed by the rate of detritiation of [2-3H]- and [3-3H]glucose, by lactate output and by the changes in glycogen content. A 20-40% increase in Fru-2,6-P2 content was observed when glycolysis was stimulated by increasing either the workload (by increasing both preload and afterload) or the concentration of glucose (from 2 to 11 mM), or by adding 7 microM insulin. Anoxia decreased the external work developed by the heart, stimulated glycolysis by activating glycogenolysis, but did not increase Fru-2,6-P2. The increase of Fru-2,6-P2 content observed after insulin, high workload or glucose load might be related to a stimulation of glucose transport, and/or an activation of 6-phosphofructo-2-kinase (PFK-2), the enzyme responsible for the synthesis of Fru-2,6-P2. Addition to the perfusate of 0.5 to 10 mM lactate, which is a preferred substrate for the heart, with pyruvate in a 10:1 ratio, induced a dose-dependent inhibition of the glycolytic flux through PFK-1, with a maximal inhibition of 75% at 5 mM lactate. The accumulation of hexose 6-phosphates without change in fructose 1,6-bisphosphate and triose-phosphates concentrations confirmed that the inhibition of glycolysis was mainly exerted on PFK-1. This inhibition resulted from a doubling of the citrate concentration, an inhibitor, and from 75% decrease in Fru-2,6-P2. Despite the inhibition of glycolysis, glucose phosphorylation was barely affected by lactate, suggesting a change in glucose metabolism. Indeed, lactate induced a dose-dependent increase in glycogen content, which doubled at 5 mM lactate, reaching the level obtained after addition of 7 microM insulin. Increased glycogen synthesis was explained by the accumulation of UDP glucose, the substrate, and glucose 6-phosphate, a stimulator of glycogen synthase. We conclude that, during aerobiosis, Fru-2,6-P2 can be regarded as a glycolytic signal which is switched on by glucose availability, workload and insulin, and which is switched off by the availability of alternative oxidative substrates such as lactate. The latter also controls glucose metabolism by diverting glucose from glycolysis to glycogen synthesis.

Animals↗
PubMed1993

Inhibition of glycolysis by amino acids in ascites tumor cells. Specificity and mechanism.

The effect of glutamine and asparagine on glucose metabolism has been studied in ascites tumor cells. Either of these amino acids decreased the glycolytic flux about 80%. Half-maximal effects were obtained with 0.14 mM glutamine and 0.087 mM asparagine. Among the 20 L-amino acids, only glutamate produced a similar effect. Glutamine and asparagine caused a 70% increase of hexose monophosphates and a large decrease of fructose-1,6-P2 and triose phosphates, evidencing a strong inhibition of the phosphofructokinase (EC 2.7.11) reaction. Analysis of the levels of various phosphofructokinase effectors revealed that fructose-2,6-P2 and AMP decreased 4-fold, phosphoenolpyruvate, citrate, and ATP increased 4-, 3-, and 1.8-fold, respectively, and that there was no change in ADP, Pi, and intracellular pH. Assay of phosphofructokinase at concentrations of substrates and effectors determined to be in the cells showed that the low activity of this enzyme could be accounted for by the change in the concentration of effectors, the major mechanism being the change in adenine nucleotides. The decrease in fructose-2,6-P2 contributed very little to the inhibition of phosphofructokinase activity. The effects of amino acids were prevented by amino-oxyacetate, suggesting that transamination was an obligatory step for these changes.

Amino Acids↗
PubMed1993

Role of fructose 2,6-bisphosphate in the control of heart glycolysis.

The aim of this work was to study whether changes in fructose 2,6-bisphosphate concentration are correlated with variations of the glycolytic flux in the isolated working rat heart. Glycolysis was stimulated to different extents by increasing the concentration of glucose, increasing the workload, or by the addition of insulin. The glycolytic flux was measured by the rate of detritiation of [2-3H]- and [3-3H]glucose. Under all the conditions tested, an increase in fructose 2,6-bisphosphate content was observed. The glucose- or insulin-induced increase in fructose 2,6-bisphosphate content was related to an increase in the concentration of fructose 6-phosphate, the substrate of 6-phosphofructo-2-kinase. An increase in the workload correlated with a 50% decrease in the Km of 6-phosphofructo-2-kinase for fructose 6-phosphate. Similar changes in Km have been observed when purified heart 6-phosphofructo-2-kinase was phosphorylated in vitro by the cyclic AMP-dependent protein kinase or by the calcium/calmodulin-dependent protein kinase. Since the concentration of cyclic AMP was not affected by increasing the workload, it is possible that the change in Km of 6-phosphofructo-2-kinase, which was found in hearts submitted to a high load, resulted from phosphorylation by calcium/calmodulin protein kinase; other possibilities are not excluded. Anoxia decreased the external work developed by the heart, stimulated glycolysis and glycogenolysis, but did not increase fructose 2,6-bisphosphate.

Animals↗
PubMed1995

In vitro inhibition of rat heart sarcoplasmic reticular membrane ATPase activities by amphotericin B and their reversal by fructose-1,6-diphosphate.

The effect of amphotericin B on rat heart sarcoplasmic reticular membrane Na(+)-K+ and Ca2+ ATPase activities in vitro was investigated. Amphotericin B in selected concentrations of 100-1000 ng significantly inhibited the sarcoplasmic reticular membrane ATPase activities studied. Fructose-1,6-diphosphate (1000 microM concentration) completely reversed the inhibition of Ca2+ ATPase activity in particular, but failed to reverse that of Na+(-)K+ATPase activities at 1000 microM concentration. Fructose-1,6-diphosphate may afford some protection against 1000 ng amphotericin B-induced myocardial toxicity. These damages may vary depending upon the dose of amphotericin B used in experimental studies.

Adenosine Triphosphatases↗
PubMed1995

The phosphofructokinase-uncharged tRNA interaction in metabolic and cell cycle control: an interpretive review.

When the tRNA of mammalian cells is incompletely charged due to amino acid deficiency or by analogs which cannot be activated, many metabolic events become limited. This rapid demise of cell function appears to be because of the inhibition of phosphofructokinase (PFK) by uncharged tRNA (FEBS Lett. 302: 113 (1992)). Charged tRNA has been shown to be "sequestered within the protein synthetic machinery", (Negrutskii, B.S. and Deutscher, M.P., Proc. Natl. Acad. Sci. USA 89 3601 (1992) and would therefore be removed from an inhibitory role. Besides the direct demonstration that tRNA inhibits PFK in an assay regarded as indicative of its control mechanism, several reports in the literature support this model. These include 1) The rapid onset of inhibition of glycolysis and glucose uptake by intact cells upon amino acid deficiency and the similar lesion at the 43S ribosomal subunit on glucose or amino acid deprivation. 2) The recognition that unusually high concentrations of cAMP required to stimulate protein synthesis in energy depleted or gel filtered lysates correlates with its action on PFK as an analog of the positive effector, adenosine-5'-monophosphate. 3)The often repeated observation that the product of PFK activity, fructose-1,6-diphosphate, is a stimulant of protein synthesis (see Jackson, R.J., et al. Eur. J. Biochem. 131: 289-313 (1983)). This diphosphate has been shown to be the proximate effector binding to eIF-2B, the guanine nucleotide exchange factor (Singh, L.P. Arror, A.R. and Wahba, A.J., FASEB J. 8 279 (1994)) which by releasing GDP bound to the inactive GDP:eIF-2 complex, permits the factor to initiate a new peptide chain. The above information supports the view that the block at the G1 restriction point in the cell cycle of normal cells brought about by amino acid deprivation is a result of inhibition of protein synthesis through the phosphofructokinase-uncharged tRNA mechanism. This is consistent with observations in the literature that tumor and transformed cells, which are more resistant to this block (Pardee, A.B., Proc. Natl. Acad. Sci. U.S.A. 71:1286-1291 (1974)) have a higher phosphofructokinase activity or higher levels of fructose-1,6-diphosphate.

Amino Acids↗
PubMed1995

Gluconeogenesis during hypoxia in vascular smooth muscle studied by 13C-NMR.

We investigated whether hypoxia altered the utilization of fructose-1,6-bisphosphate as a gluconeogenic or glycolytic intermediate in superfused media from hog carotid artery. Using 13C-NMR, we found that although 3-13C-lactate production from 1-13C-glucose increased compared to that under well-oxygenated conditions, the conversion of exogenously applied 1,6-13C-fructose-1,6-bisphosphate to glucose (gluconeogenesis) or to 3-13C-lactate was not significantly affected by hypoxia. Since hypoxia alters the rate of glucose conversion to lactate but not the conversion of fructose-1,6-bisphosphate to glucose, we conclude that glycolysis and glycogenolysis may continue to be compartmentalized during hypoxia and that a high rate of gluconeogenesis can occur even during hypoxia.

Animals↗
PubMed1987

Function, structure and evolution of fructose-1,6-bisphosphatase.

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate is a key reaction of carbohydrate metabolism. The enzyme that catalyzes this reaction, fructose-1,6-bisphosphatase, appears to be present in all forms of living organisms. Regulation of the enzyme activity, however, occurs by a variety of distinct mechanisms. These include AMP inhibition (most sources), cyclic AMP-dependent phosphorylation (yeast), and light-dependent activation (chloroplast). In this short review, we have analyzed the function of several fructose-1,6-bisphosphatases and we have made a comparison of partial amino acid sequences obtained from the enzymes of the yeast Saccharomyces cerevisiae, Escherichia coli, and spinach chloroplasts with the known entire amino acid sequence of a mammalian gluconeogenic fructose-1,6-bisphosphatase. These results demonstrate a very high degree of sequence conservation, suggesting a common evolutionary origin for all fructose-1,6-bisphosphatases.

Amino Acid Sequence↗
PubMed1996

Protection of astrocytes by fructose 1,6-bisphosphate and citrate ameliorates neuronal injury under hypoxic conditions.

Fructose 1,6-bisphosphate (FBP) protects astrocytes from hypoxic injury in vitro. To determine whether FBP and citrate (inhibitors of phosphofructokinase) ameliorate hypoxia-induced injury to neurons and, if they do, whether the protective effects are a direct result of their actions on neurons or a consequence of their actions on astrocytes, we added FBP or citrate to the media of normoxic and hypoxic 'pure', mixed and co-culture systems. FBP (3.5 mM) and citrate (10 microM-2 mM) decreased release of LDH from astrocytes following 24 h of hypoxia. Eight hours of hypoxia killed pure neuronal cultures and neither FBP nor citrate prevented this death. However, in mixed and co-culture systems, FBP and citrate increased neuronal viability (as determined by the ratio of live-to-total cells), even after 47 h of hypoxia. In co-culture, following 24 h of hypoxia, both FBP and citrate reduced neuronal release of LDH and neuronal death. Fluorocitrate, a suicidal-inhibitor of aconitase, also protected astrocytes, but not neurons, from hypoxia in 'pure' culture, presumably by increasing intracellular citrate concentrations through inhibition of the catalysis of citrate to isocitrate We conclude that FBP and citrate attenuate hypoxic neuronal injury through their effects on astrocytes.

Animals↗
PubMed1996

Improved liver function following infusion of fructose-1, 6-bisphosphate in posthepatectomy patients.

The clinical effect of fructose-1,6-bisphosphate (FBP) administered to posthepatectomy patients was examined. FBP at 0.25 mmol/kg was administered continuously into the hepatic artery for 60 minutes on the 1st postoperative day in 11 cases. Hepatic arterial infusion of 0.25 mmol/kg glucose was performed in 7 cases. Furthermore, in 10 cases in which a catheter was not inserted in to the hepatic artery, 0.25 mmol/kg FBP was administered intravenously over a 60-minute period. Arterial ketone body ratio (AKBR) and serum levels of cyclic adenosine monophosphate, immunoreactive insulin, inorganic phosphorus, glucose, fructose, pyruvate, lactate and pyruvate kinase (PK) in the arterial blood were measured before and after administration. AKBR hardly changed after hepatic arterial infusion of glucose. It rose until 3 hours after intravenous or intrahepatic arterial administration of FBP. Especially, after hepatic arterial infusion of FBP, the AKBR was significantly higher up to 2 hours after administration than that before administration (P < 0.01). With hepatic arterial infusion of FBP, serum pyruvate transiently increased immediately after infusion (P < 0.01). PK activity was significantly elevated after administration of FBP (P < 0.05). Serum lactate levels decreased significantly after hepatic arterial infusion of FBP (P < 0.05). There was no difference in the recovery of protein synthetic ability and the postoperative changes in serum liver function test values among the three groups. Hepatic arterial infusion of FBP was suggested to promote adenosine triphosphate production by acceleration of the glycolytic pathway and lactate uptake in the hepatic cell.

Blood Glucose↗
PubMed1977

[Glycolysis in the eye tissues of the rabbit in ontogeny. II. The dynamics of the changes in the level of glycolysis and lactic acid intermediates].

The level of intermediates of glycolysis (hexose monophosphates, fructose-1,6-diphosphate, pyruvate) and the rate of lactic acid synthesis (under the aerobic conditions without substrates and in the presence of glucose, glucose-6-phosphate and fructose-1,6-diphosphate) were measured in the eye tissues (retina, iris, ciliary bodies, uvea) of rabbits of different age. The rate of lactic acid synthesis under the aerobic conditions in the retina and uveal tract increases of the latter the rate of lactic acid synthesis was the highest. The greatest increase in the lactic acid content was observed during the first 15 days of postnatal development.

Aerobiosis↗
PubMed1997

Protection from amphotericin B-induced lipid peroxidation in rats by fructose-1,6-diphosphate.

Amphotericin B's (Amp B) usefulness is associated with a number of toxic cellular side effects. We investigated the in vivo effects of Amp B on the lipid peroxide (malondialdehyde [MDA]) levels in various organs of rats infused with 1.5 mg/kg body weight of Amp B. The rats (n = 8) experienced cardiac arrest following Amp B infusion. Among the organs, the kidney exhibited higher levels of MDA and was followed by brain > liver > lung > heart. Pretreatment of rats with 0.35 g/kg body weight of fructose-1,6-diphosphate (FDP) prior to Amp B infusion reduced the extent of MDA formation in all organs. These studies suggest that Amp B-associated toxicity in rats may involve the formation of lipid peroxide damage and FDP, in part by reducing these effects, may afford partial protection.

Amphotericin B↗